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| Subject Categories: Cell & Tissue Architecture | Molecular Biology of Disease |
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| The EMBO Journal
(2005) 24, 3400–3410, doi:10.1038/sj.emboj.7600809 Published online 8 September 2005 |
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Wound-healing defect of CD18-/- mice due to a decrease in TGF- 1 and myofibroblast differentiation |
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| Thorsten Peters1, 7, Anca Sindrilaru1, 7, Boris Hinz2, Ralf Hinrichs1, André Menke3, Ezz Al Din Al-Azzeh1, Katrin Holzwarth4, Tsvetelina Oreshkova1, Honglin Wang1, Daniel Kess1, Barbara Walzog5, Silke Sulyok1, Cord Sunderkötter1, Wilhelm Friedrich6, Meinhard Wlaschek1, Thomas Krieg4 and Karin Scharffetter-Kochanek1 |
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1 Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany 2 Laboratory of Cell Biophysics, École Polytechnique Féderale de Lausanne, Lausanne, Switzerland 3 Department of Internal Medicine, University of Ulm, Ulm, Germany 4 Department of Dermatology, University of Cologne, Cologne, Germany 5 Department of Physiology, Ludwig-Maximilians-Universität, Munich, Germany 6 Department of Pediatrics, University of Ulm, Ulm, Germany To whom correspondence should be addressed Karin Scharffetter-Kochanek, Department of Dermatology and Allergic Diseases, University of Ulm, Maienweg 12, 89081 Ulm, Germany. Tel.:+49 731 500 21801; Fax: +49 731 500 21870; E-mail: karin.scharffetter-kochanek@medizin.uni-ulm.de 7 These authors contributed equally to this work Received 13 December 2004; Accepted 19 August 2005; Published online 8 September 2005. |
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| Abstract |
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We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18-/- mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers  -smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18-/- mice, suggesting an impaired myofibroblast differentiation. TGF- signalling was clearly involved since TGF-1 and TGF- receptor type-II protein levels were decreased, while TGF-1 injections into wound margins fully re-established wound closure. Since, in CD18-/- mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18-/- neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-1. Indeed, in neutrophil–macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing. |
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| Keywords: cellular differentiation, growth factors, integrins, myofibroblast, wound healing |
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